Furan compounds are cyclic dienic ethers, manufactured commercially through decarbonylation of furfural over palladium/charcoal. Furan and isoxazoline derivatives belong to important classes of pharmacophores found in a large number of natural products and are present in many therapeutic agents (Chen, I. J.; et al. Planta Med. 2006, 72, 351; Faulkner, D. J. Nat. Prod. Rep. 1984, 1, 251; Usui, T.; et al. J. Antibiot. 1971, 24, 93; Bindseil, K. U.; et al. Helv. Chim. Acta 1991, 74, 1281; Sakai, R.; et al. J. Am. Chem. Soc. 1997, 119, 4112; Encamacion, R. D.; et al. J. Nat. Prod. 2000, 63, 874; Fattorusso, E.; et al. J. Chem. Soc., Chem. Commun. 1970, 752; Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1; Benharref, A.; Pais, M. J. Nat. Prod. 1996, 59, 177; Nicholas, O. M.; et al. Org. Lett. 2001, 3, 1543). Furan derivatives have been used as a building block for a large number of heterocyclic substructures and also as synthons in natural product synthesis (Wright, D. L. Prog. Heterocycl. Chem. 2005, 17, 1). These compounds are important forming components of lacquers, resin solvents, agricultural chemicals, lubricating oils, wetting agents, plastics, cements, and pharmaceuticals. Furan is also a precursor of tetrahydrofuran, which is a valuable solvent and itself a precursor to pyrrolidines and thiolanes. Isoxazoline derivatives also have great biological importance, for example, many GPII/IIIa inhibitors and human leukocyte elastase (HLE) inhibitors also have an isoxazoline skeleton (Mousa, S. A.; et al. J. Cardiovasc. Pharmacol. 1998, 32, 169; Groutas, W. C.; et al. Bioorg. Med. Chem. 1995, 3, 125). Isoxazoline derivatives have also been incorporated in fullerenes rendering special properties as nanoscale connectors in molecular electronic devices (Lee, H. M.; Lee, C.; Cho, M.; Hwang, Y. G.; Lee, K. H. Bull. Korean Chem. Soc. 2004, 25, 1850). Because of the importance of furans, significant research has been undertaken to develop more efficient processes of generating furan compounds.
The use of palladium catalysts in carbon-carbon and carbon-heteroatom bond forming reactions has been of great synthetic utility (Tsuji, J.; et al. Tetrahedron Lett. 1965, 6, 4387; Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292; Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecules; University Science Books Sausalito, Calif., 1999; Li, J. J.; Gribble, O. W. Palladium in Heterocyclic Chemistry. A Guide for the Synthetic Chemist; Pergamon: Amsterdam and New York, N.Y., 2000; Vol. 20; Nicolaou, K. C.; et al. Angew. Chem., Int. Ed. 2005, 44, 4442; Zeni, G.; Larock, R. Chem. Rev. 2004, 104, 2285). For example, palladium(0) catalyzed reaction of dimethyl (Z)-2-butenylene dicarbonate with dimethyl malonate led to formation of the (R)-dimethyl 2-vinylcyclopropane-1,1-dicarboxylate (compound 1), seen in FIG. 1, though in low enantiomeric excess (67%; Hayashi, et al. Tetrahedron Lett. 1988, 29, 66). The reaction of methyl acetyl acetate or acetylacetone with 2-butenylene dicarbonate, which led to formation of a trisubstituted furan derivative (compound 2), seen in FIG. 1, was also observed. The formation of compounds 1 and 2 has been rationalized through a nucleophilic attack of the enolate carbon leading to the C—C bond formation in 1 and the enolate oxygen leading to the formation of the C—O bond in compound 2 (Hayashi, et al. Tetrahedron Lett. 1988, 29, 66). In another example of the carbon heteroatom bond formation, the formation of compounds 3 and 4, seen in FIG. 1, was reported through Pd(0)-mediated alkylation (Yoshizaki, et al. J. Org. Chem. 1995, 60, 2016). The formation of isoxazoline-2-oxide, compound 5, upon reaction of lithium [(phenylsulfonyl)methylene]nitronate with cis-1,4-diacetoxycyclopent-2-ene in the presence of Pd(0) catalysts, seen in FIG. 1, was observed (Trost, B. M.; et al. J. Am. Chem. Soc. 1992, 114, 8745). However, these present methods suffer from the ambivalent nature of the nitro-stabilized anions, permitting both C and O alkylations.
There is a lack of convenient methods for the preparation of these furan and isoxazoline derivatives. The general strategy for synthesis of these five-membered nitronates (isoxazoline-2-oxides) involves cyclization of γ-functionalized nitro compounds (Kunetsky, R. A.; et al. Synthesis 2006, 13, 2265; Kunetsky, R. A.; et al. Org. Lett. 2003, 5, 4907), which themselves require tedious preparation. An alternative synthesis involves [3+2]cycloaddition of nitrile oxides with olefins (Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; Feuer, H., Ed.; VCH: Weinheim, 1988; pp 55-74), which suffers from rapid dimenization of nitrile oxides to form furoxan N-oxide (Whitney, R. A.; Nicholas, E. S. Tetrahedron Lett. 1981, 35, 3371). As such, new methods are needed to prepare furan and isoxazoline derivative.